AZACITIDINE SANDOZ 25 mg/mL POWDER FOR INJECTABLE SOLUTION

Introduction

PACKAGE LEAFLET

Package Leaflet:Information for the User

Azacitidina Sandoz 25 mg/ml powder for injectable suspension EFG

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if they are not listed in this leaflet. See section 4.

Contents of the pack

1. What Azacitidina Sandoz is and what it is used for
2. What you need to know before you use Azacitidina Sandoz
3. How to use Azacitidina Sandoz
4. Possible side effects

5 Conservation of Azacitidina Sandoz

1. Contents of the pack and further information

1. What Azacitidina Sandoz is and what it is used for

What Azacitidina Sandoz is

This medicine is an anticancer agent that belongs to a group of medicines called "antimetabolites". This medicine contains the active substance "azacitidine".

What Azacitidina Sandoz is used for

Azacitidine is used in adults who cannot receive a stem cell transplant to treat:

• High-risk myelodysplastic syndromes (MDS).
• Chronic myelomonocytic leukemia (CMML).
• Acute myeloid leukemia (AML).

These diseases affect the bone marrow and can cause problems with the normal production of blood cells.

How Azacitidina Sandoz works

Azacitidine works by preventing the growth of cancer cells. Azacitidine is incorporated into the genetic material of cells (ribonucleic acid [RNA] and deoxyribonucleic acid [DNA]). It is believed to work by altering the way cells activate or deactivate genes by interfering with the production of new RNA and DNA. It is believed that these actions correct the problems of maturation and growth of healthy blood cells in the bone marrow that cause myelodysplastic disorders, and that kill cancer cells in leukemia.

Ask your doctor or nurse if you have any questions about how azacitidine works or why you have been prescribed this medicine.

2. What you need to know before you use Azacitidina Sandoz

Do not use Azacitidina Sandoz

• If you are allergic to azacitidine or any of the other ingredients of this medicine (listed in section 6).
• If you have advanced liver cancer.
• During breastfeeding.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before starting treatment with azacitidine:

• If you have a low platelet count, red blood cells, or white blood cells.
• If you have kidney disease.
• If you have liver disease.
• If you have ever had heart disease or a heart attack, or have a history of lung disease.

Azacitidine may cause a severe immune reaction called "differentiation syndrome" (see section 4).

Blood tests

Before starting treatment with azacitidine and at the start of each treatment period (called a "cycle"), you will have blood tests. This is to check that you have enough blood cells and that your liver and kidneys are working properly.

Children and adolescents

The use of azacitidine is not recommended in children and adolescents under 18 years of age.

Other medicines and Azacitidina Sandoz

Tell your doctor or pharmacist if you are using, have recently used, or might use any other medicines. This is because azacitidine may affect the way other medicines work. Similarly, other medicines may affect the way azacitidine works.

Pregnancy, breastfeeding, and fertility

Pregnancy

You should not use azacitidine during pregnancy because it may harm the baby.

If you are a woman who can become pregnant, you must use an effective contraceptive method while you are being treated with azacitidine and for 6 months after finishing treatment with azacitidina.

Tell your doctor immediately if you become pregnant during treatment.

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, ask your doctor or pharmacist for advice before using this medicine.

Breastfeeding

Azacitidine should not be used during breastfeeding. It is not known if this medicine is excreted in breast milk.

Fertility

Men should not father a child while being treated with azacitidine.

Men must use an effective contraceptive method while using azacitidine and for 3 months after finishing treatment with azacitidina.

Ask your doctor if you want to preserve your sperm before being treated with this medicine.

Driving and using machines

Do not drive or use tools or machines if you experience side effects such as fatigue.

3. How to use Azacitidina Sandoz

Before administering azacitidine, your doctor will give you another medicine to prevent nausea and vomiting at the start of each treatment cycle.

• The recommended dose is 75 mg/m2 of body surface area. Your doctor will decide your dose of this medicine based on your general condition, height, and weight. Your doctor will monitor your progress and, if necessary, may change your dose.
• Azacitidine is given every day for a week, followed by a three-week rest period. This "treatment cycle" is repeated every four weeks. You will usually receive at least six cycles of treatment.

A doctor or nurse will give you this medicine as an injection under the skin (subcutaneously). It can be given under the skin of the thigh, abdomen, or upper arm.

If you have any further questions about the use of this medicine, ask your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor immediately if you notice any of the following side effects:

• Drowsiness, tremors, jaundice, abdominal swelling, and easy bruising.These may be symptoms of liver failure and can be potentially life-threatening.
• Swelling of legs and feet, back pain, decreased urine output, increased thirst, rapid pulse, dizziness, and nausea, vomiting, or decreased appetite and feeling of confusion, restlessness, or fatigue.These may be symptoms of kidney failure and can be potentially life-threatening.
• Fever.This could be due to an infection as a result of having low white blood cell counts, which can be potentially life-threatening.
• Chest pain or difficulty breathing that may be accompanied by fever.This may be due to a lung infection known as "pneumonia" and can be potentially life-threatening.
• Bleeding.For example, blood in the stool due to bleeding in the stomach or intestine, or bleeding in the head. These may be symptoms of having low platelet counts in the blood.
• Difficulty breathing, swelling of the lips, itching, or skin rash.These may be due to an allergic reaction (hypersensitivity).

Other side effects include:

Very common side effects(may affect more than 1 in 10 people)

• Decreased red blood cell count (anemia). You may feel tired and pale.
• Decreased white blood cell count. This may be accompanied by fever. You are also more likely to get infections.
• Low platelet count in the blood (thrombocytopenia). You are more prone to bleeding and bruising.
• Constipation, diarrhea, nausea, vomiting.
• Pneumonia.
• Chest pain, difficulty breathing.
• Fatigue (fatigue).
• Reaction at the injection site, including redness, pain, or skin rash.
• Loss of appetite.
• Joint pain.
• Bruising.
• Skin rash.
• Red or purple spots under the skin.
• Abdominal pain.
• Itching.
• Fever.
• Nose and throat pain.
• Dizziness.
• Headache.
• Sleeping problems (insomnia).
• Nosebleeds (epistaxis).
• Muscle pain.
• Weakness (asthenia).
• Weight loss.
• Low potassium levels in the blood.

Common side effects(may affect up to 1 in 10 people)

• Bleeding in the head.
• Blood infection caused by bacteria (sepsis). This may be due to low white blood cell counts in the blood.
• Bone marrow failure. This may cause low red and white blood cell counts and platelets.
• A type of anemia where there is a decrease in red and white blood cells and platelets.
• Urinary tract infection.
• A viral infection that causes herpes-like lesions.
• Bleeding from the gums, stomach, or intestine, or bleeding in the back due to hemorrhoidal bleeding, bleeding in the eyes, bleeding under the skin or within the skin (hematoma).
• Blood in the urine.
• Ulcers in the mouth or tongue.
• Changes in the skin at the injection site. These may be swelling, a hard lump, bruising, bleeding into the skin (hematoma), skin rash, itching, and changes in skin color.
• Redness of the skin.
• Skin infection (cellulitis).
• Nose and throat infection, or sore throat.
• Pain or excessive discharge from the nose or sinuses (sinusitis).
• High or low blood pressure (hypertension or hypotension).
• Difficulty breathing when moving.
• Pain in the throat and larynx.
• Indigestion.
• Drowsiness (lethargy).
• Feeling unwell.
• Anxiety.
• Feeling confused.
• Hair loss.
• Kidney failure.
• Dehydration.
• A white coating on the tongue, inside of the cheeks, and sometimes the palate, gums, and tonsils (fungal infection in the mouth).
• Fainting.
• Decrease in blood pressure when standing up (orthostatic hypotension) that causes dizziness when standing up or sitting.
• Sleepiness, drowsiness (somnolence).
• Bleeding due to the catheter.
• A disease that affects the intestine that can cause fever, vomiting, and abdominal pain (diverticulitis).
• Fluid around the lungs (pleural effusion).
• Chills (shivering).
• Muscle spasms.
• Itchy skin rash (urticaria).
• Fluid around the heart (pericardial effusion).

Uncommon side effects(may affect up to 1 in 100 people)

• Allergic reaction (hypersensitivity).
• Shivering.
• Liver failure.
• Painful, large, and swollen purple spots on the skin and fever.
• Painful ulcers on the skin (pyoderma gangrenosum).
• Inflammation of the lining that surrounds the heart (pericarditis).

Rare side effects(may affect up to 1 in 1,000 people)

• Dry cough.
• Painless swelling of the fingertips (drumstick fingers).
• Tumor lysis syndrome - metabolic complications can occur during cancer treatment and sometimes even without treatment. These complications occur as a result of the product of dying cancer cells and may include: changes in blood biochemistry, high levels of potassium, phosphorus, uric acid, and low levels of calcium, which in turn generate changes in kidney function and heart rhythm, seizures, and sometimes death.

Frequency not known(cannot be estimated from the available data)

• Infection of the deep layers of the skin, which spreads rapidly damaging the skin and tissue, which can be potentially life-threatening (necrotizing fasciitis).
• Severe immune reaction (differentiation syndrome) that can cause fever, cough, difficulty breathing, skin rash, decreased urine output, low blood pressure (hypotension), swelling of the arms or legs, and rapid weight gain.
• Inflammation of blood vessels in the skin that can cause skin rash (cutaneous vasculitis).

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if they are not listed in this leaflet. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaram.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Conservation of Azacitidina Sandoz

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and vial label after EXP. The expiry date is the last day of the month stated.

Your doctor, pharmacist, or nurse is responsible for the storage of azacitidine. They are also responsible for the proper preparation and disposal of unused medicine.

For unopened vials of this medicine:

This medicine does not require special storage conditions.

If used immediately

The suspension should be administered within 60 minutes of preparation.

If used later

If the azacitidina suspension is prepared using non-refrigerated water for injections, the suspension should be placed in the refrigerator (between 2°C and 8°C) immediately after preparation and should be kept in the refrigerator for up to 24 hours.

If the azacitidina suspension is prepared using refrigerated water for injections (between 2°C and 8°C), the suspension should be placed in the refrigerator (between 2°C and 8°C) immediately after preparation and should be kept in the refrigerator for up to 36 hours stored in the vial and up to 30 hours between 2°C and 8°C if stored in the syringe.

The suspension should be allowed to reach room temperature (20°C to 25°C) up to 30 minutes before administration.

Do not use this medicine if the suspension contains large particles.

6. Container Contents and Additional Information

Composition of Azacitidine Sandoz

• The active ingredient is azacitidine. One vial contains 100 mg of azacitidine. After reconstitution with 4 ml of water for injectable preparations, the reconstituted suspension contains 25 mg/ml of azacitidine.
• The other component is mannitol (E421).

Appearance of the Product and Container Contents

Azacitidine Sandoz is a white powder for injectable suspension and is supplied in a glass vial with a rubber stopper and an aluminum seal with a plastic cap, containing 100 mg of azacitidine. The vial is stored in a cardboard box.

Package size: 1 vial.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Sandoz Farmacéutica, S.A.

Centro Empresarial Parque Norte

Edificio Roble

C/ Serrano Galvache, 56

28033 Madrid

Spain

Manufacturer

Pharmadox Healthcare Ltd,

KW20A Kordin Industrial Park

Paola, PLA3000

Malta

or

LEK farmacevtska družba d.d. (Lek Pharmaceuticals d.d.)

Verovškova ulica 57

1526 Ljubljana

Slovenia

or

Salutas Pharma GmbH

Otto-von-Guericke-Allee 1

Barleben, Sachsen-Anhalt, 39179

Germany

Date of the Last Revision of thisLeaflet:January 2024.

Detailed information on this medicinal product is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/

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This information is intended only for healthcare professionals:

Recommendations for Safe Handling

Azacitidine is a cytotoxic medicinal product and, as with other potentially toxic compounds, caution should be exercised when handling and preparing azacitidine suspensions. The procedures for the correct handling and disposal of anticancer medicinal products should be applied.

If reconstituted azacitidine comes into contact with the skin, the area should be washed immediately and thoroughly with water and soap. If it comes into contact with mucous membranes, it should be rinsed thoroughly with water.

Incompatibilities

This medicinal product should not be mixed with other medicinal products, except those mentioned below (see "Reconstitution Procedure").

Reconstitution Procedure

Azacitidine Sandoz should be reconstituted with water for injectable preparations. The validity period of the reconstituted medicinal product can be extended by reconstituting it with refrigerated water for injectable preparations (between 2 °C and 8 °C). The following information is provided on the storage of the reconstituted medicinal product.

1. The following elements should be assembled:

Vial(s) of azacitidine; vial(s) of water for injectable preparations; non-sterile surgical gloves; alcohol-impregnated swabs; 5 ml injection syringe(s) with needle(s).

1. 4 ml of water for injectable preparations should be drawn into the syringe, ensuring that any trapped air is purged from the syringe.
2. The needle of the syringe containing the 4 ml of water for injectable preparations should be inserted through the rubber stopper of the azacitidine vial; then, the water for injectable preparations should be injected into the vial.
3. After removing the syringe and needle, the vial should be shaken vigorously until a uniform, turbid suspension is obtained. After reconstitution, each ml of suspension will contain 25 mg of azacitidine (100 mg/4 ml). The reconstituted product is a turbid and homogeneous suspension, without agglomerates. The product should be discarded if it contains large particles or agglomerates. The suspension should not be filtered after reconstitution, as this could remove the active ingredient. It should be noted that some adapters, perfusion needles, and closed systems contain filters; therefore, such systems should not be used for the administration of the medicinal product after reconstitution.
4. The rubber stopper should be cleaned and a new syringe with a needle should be inserted into the vial. Then, the vial should be inverted, ensuring that the tip of the needle is below the level of the liquid. The plunger should then be pulled back to withdraw the required amount of medicinal product for the correct dose, ensuring that any trapped air is purged from the syringe. Then, the syringe with the needle should be withdrawn from the vial and the needle should be discarded.
5. A new subcutaneous needle (25 gauge is recommended) should be firmly attached to the syringe. The needle should not be purged before injection, in order to reduce the incidence of local reactions at the injection site.
6. If more than 1 vial is required, all the above steps should be repeated for the preparation of the suspension. In the case of doses for which more than 1 vial is required, the dose should be divided into equal parts, for example, a dose of 150 mg = 6 ml; 2 syringes with 3 ml in each syringe. Due to retention in the vial and needle, it may not be possible to withdraw all the suspension from the vial.
7. The contents of the dosing syringe should be re-suspended immediately before administration. The syringe with the reconstituted suspension should be allowed to reach room temperature (approximately between 20 °C and 25 °C) up to 30 minutes before administration. If the time elapsed is more than 30 minutes, the suspension should be discarded properly and a new dose prepared. To re-suspend, the syringe should be rolled vigorously between the palms of the hands until a uniform, turbid suspension is obtained. The product should be discarded if it contains large particles or agglomerates.

Storage of the Reconstituted Medicinal Product

When azacitidine is reconstituted using water for injectable preparations that has not been refrigerated, the chemical and physical stability of the reconstituted medicinal product has been demonstrated at 25 °C for 60 minutes and between 2 °C and 8 °C for 24 hours when stored in the vial and syringe.

The validity period of the reconstituted medicinal product can be extended by reconstituting it with refrigerated water (between 2 °C and 8 °C) for injections. When azacitidine is reconstituted using refrigerated water (between 2 °C and 8 °C) for injections, the chemical and physical stability of the reconstituted medicinal product has been demonstrated between 2 °C and 8 °C for 36 hours when stored in the vial and for 30 hours between 2 °C and 8 °C when stored in the syringe.

From a microbiological point of view, the reconstituted product should be used immediately. If not used immediately, the in-use storage times and conditions are the responsibility of the user and should not exceed 24 hours between 2 °C and 8 °C.

Calculation of an Individual Dose

The total dose, according to body surface area (BSA), can be calculated as follows:

Total dose (mg) = dose (mg/m2) × BSA (m2)

The following table is presented only as an example of how to calculate individual doses of azacitidine based on an average BSA value of 1.8 m2.

Method of Administration

Do not filter the suspension after reconstitution.

Reconstituted Azacitidine Sandoz should be injected subcutaneously (insert the needle at an angle of 45 to 90°) with a 25-gauge needle in the upper arm, thigh, or abdomen.

Doses greater than 4 ml should be injected at two separate sites.

The injection sites should be rotated. New injections should be administered at least 2.5 cm away from the previous site and never in sensitive areas, with hematomas, redness, or hardening.

The disposal of unused medicinal products and all materials that have come into contact with them should be carried out in accordance with local regulations.